Genetics has been implicated in the etiology of bipolar affective disorder by a variety of epidemiological data, including studies of twins, adoptees and families. Until recently, however, attempts to identify a specific locus or mode of ingeritance have been largely inconclusive or inconsistent. Similarly, attempts to identify responsible genes through an elucidation of pathophysiological mechanisms have been unsuccessful. The recent development of molecular biological methods to detect polymorphic DNA markers has made possible the identification of chromosomal loci linked to genes for illnesses of obscure pathophysiology. Application of these methods to bipolar disorder has led to reports of linkage to two regions: 11p15 and Xq28. Subsequent inability to replicate these findings in other families has been interpreted as evidence that bipolar disorder is genetically heterogeneous. The study proposed here is designed to detect linkage to at least one gene for bipolar disorder in the presence of heterogeneity. Specifically, it will test the hypothesis that bipolar disorder is transmitted through several single major loci, one of which is present in 50% of families. This is a large task which will only be begun through the resources requested in this proposal. The long range goal is to identify 40 families with four or more affected members each and screen the genome with 300-500 markers. Towards this long range goal, resources are requested in this proposal to identify 20 families and map 100 loci. To the families ascertained in San Diego will be added another 20 families meeting criteria for this study which have been already ascertained by Drs. Ronald Remick and Adele Sadovnick at the University of British Columbia (UBC). The 20 families from San Diego will be ascertained through systematic screening of bipolar subjects presenting to UCSD hospitals and clinics. Ascertainment and diagnostic procedures will be carefully coordinated between the two sites. In both sites, spouses and their first degree relatives will be screened for the presence of affective disorder in order to exclude families possibly segregating for two separate affective disorder genes (bilineal families). Family members will be diagnosed by SCID interview and DSM-3- R criteria by personnel trained and reliability tested through the UCSD MHCRC. Lymphoblastoid cell lines will be established on all family members. Informative RFLPs of known map location will be tested for linkage to bipolar disorder by multipoint analysis using a variety of models of inheritance and several different definitions of the affected phenotype. Funding for this proposal will be used only to support the work in San Diego. Further funding will be sought in the future in order to continue the gene mapping portion of the project, and, if necessary, to expand the family collection.